Dithiocarbamates have been found to have numerous pharmaceutical utilities, for example as nitric oxide scavengers for the treatment of inflammatory and infectious diseases (See, for example, the recent work of Lai, as described in U.S. Pat. Nos. 5,714,815, 5,756,540, 5,757,532, and 5,847,004, the contents of each of which are hereby incorporated by reference in their entirety). Prior to the discovery of pharmaceutical utilities for dithiocarbamates, more traditional uses thereof include use in chemical or commercial endeavors, for example, for precipitating metals in chemical analysis or for synthesis of heterocyclic compounds (Thorn & Ludwig, The Dithiocarbamates and Related Compounds, Elsevier, Amsterdam, 1962, pages 61-126). These more traditional uses typically do not require the attributes most desired for pharmaceutical-grade dithiocarbamates, such as sterility, purity and stable, fine particulate form. The traditional methods of synthesizing dithiocarbamates are, therefore, unsuitable for preparation of pharmaceutical-grade dithiocarbamates.
The chemical nature of dithiocarbamates, which are unstable under acidic conditions, requires their preparation to be accomplished as organic or inorganic salts (Thorn & Ludwig, pages 7-42). One synthetic method for producing dithiocarbamates utilizes an organic amine, which is used in excess. However, organic amines are relatively expensive, making the production cost high. In addition, the presence of organic amine may render the resulting product dithiocarbamate unsuitable for pharmaceutical uses.
An alternative synthetic method designed to avoid use of organic amines produces the dithiocarbamate in the form of an alkali metal salt, such as a sodium salt. Since sodium salts are generally soluble in water, the solvent of choice in the preparation of dithiocarbamates by the alkali metal salt method is water (H. Xian et al., Hangzhou Daxue Xuebao, Ziran Kexueban, 9:81-84, 1982 (Chemical Abstracts 97:23417, 1982). However, side products are produced during the synthesis reaction at higher temperature, requiring the temperature of the synthesis reaction to be controlled to a temperature of no greater than about 20.degree. C. up to about 30.degree. C. to avoid undesirable side products. Therefore, the reaction temperature is usually controlled to between -5.degree. C. and 10.degree. C. (B. H. Lee et al., J. Med. Chem. 37:3154-3162, 1994).
To obtain the dithiocarbamate product in a stable solid form, organic solvent is frequently used to initiate the precipitation of the end product from the reaction mixture. Generally, methanol, acetone, or a mixture of methanol and ethanol are used as the solvent for this purpose (L. A. Shinobu et al., Acta Pharm. Toxicol. 54:189-194, 1984; P. K. Singh et al., Chem. Res. Toxicol. 7:614-620, 1994). However, methanol and acetone are toxic if ingested, rendering the products produced by this method unsuitable for use as a pharmaceutical.
Despite the knowledge in the art regarding methods for producing dithiocarbamates, there is a need for new and better methods for producing pharmaceutical-grade and/or sterile dithiocarbamates as a finely divided particulate.